Chronic renal insufficiency is a common and important health problem that causes morbidity
and mortality among patients who have undergone liver transplantation. It is mainly caused
by drugs (calcineurin inhibitors) that are used to prevent or treat rejection and once
established, there is no effective treatment. This research investigates whether L-arginine
can reverse the effects of calcineurin inhibitors on the kidneys and thus prevent renal
insufficiency in liver transplant recipients.
Although liver transplantation (LTx) is now well-established as a means of restoring health
in patients with liver failure, there remain opportunities to further optimize its outcome.
One of the major sources of mortality and morbidity in LTx recipients is renal insufficiency
associated with nephrotoxicity of immunosuppressant agents, particularly calcineurin
inhibitors (i.e., cyclosporine and tacrolimus). These agents are also associated with
hypertension and diabetes among LTx recipients, contributing to further reduction in renal
function. In a report based on nationwide data, 18% of LTx recipients developed renal
failure within 5 years.
Most of the decline in renal function after LTx occurs in the first few months. This is in
part because patients are exposed to the highest levels of calcineurin inhibitors in the
early post-LTx period, when the risk of acute cellular rejection is the greatest.
Calcineurin inhibitors produce intense renal vasoconstriction, which may be reversible early
on. Over time, however, irreversible changes, such as vascular angiopathy, tubular atrophy
and eventually interstitial fibrosis, contribute to permanent reduction in renal perfusion
and glomerular filtration. Thus, interventions to preserve renal function after LTx would
be most effective in the early post-LTx period, when most reduction in renal function occurs
and when renal vascular changes are potentially reversible.
Existing evidence and our preliminary data indicate that impairment of vasodilatory response
mediated by nitric oxide (NO) plays an important role in the pathogenesis of calcineurin
inhibitor nephrotoxicity. Our overall hypothesis is that L-arginine supplement provides
protection against calcineurin inhibitor nephrotoxicity. L-arginine, a naturally occurring
amino acid, is the main substrate of the NO synthase enzyme and exogenous supplementation of
L-arginine may improve renal perfusion by inducing renal vasodilation via increased NO
production. Although L-arginine has been shown to prevent renal damage from calcineurin
inhibitors in experimental animals, its efficacy in preserving renal function has not been
studied in human LTx recipients.
In this application, we propose to conduct a pilot, randomized, double-blinded,
placebo-controlled trial to explore the use of prophylactic L-arginine supplement in
preserving renal function in LTx recipients. Twenty-four (24) LTx recipients recovering
uneventfully from the procedure will be recruited for the study. Subjects will be
randomized 1:1 to receive 9g per day of L-arginine or placebo given orally for 7 days
between 14 and 21 days after LTx, followed by open-label maintenance with L-arginine. The
aims of the study are as follows:
AIM 1. To determine the effect of oral L-arginine supplement on glomerular filtration rate
in LTx recipients. We will compare changes in GFR, as estimated by the eGFRcys equation,
before and after a 7-day trial of L-arginine versus placebo. The eGFRcys equation has
recently been shown to be the most accurate GFR estimator incorporating serum cystatin-C and
creatinine concentrations, age, gender and race.
AIM 2. To determine the effect of L-arginine supplement on secondary efficacy endpoints.
We will compare plasma L-arginine concentrations and urinary cyclic-GMP, the latter being a
key metabolite of renal NO, between the L-arginine and placebo groups.
AIM 3. To evaluate the safety of oral L-arginine supplement in liver transplant recipients.
We will compare the frequency and severity of adverse events between the L-arginine and
AIM 4. To determine the effect of maintenance open label L-arginine on GFR. After the
7-day trial, participants will be offered an open label L-arginine for 13 additional weeks.
We will compare their GFR determined by iothalamate clearance before and after the
maintenance use of L-arginine supplement.
Our hypothesis is that L-arginine will promote the release of NO in the renal vascular bed,
increasing renal blood flow and glomerular filtration rate (AIM 1). We believe it is
critical that we test this in patients early after LTx before irreversible vascular and
glomerular damage is established. Once this proof of concept is attained, we would like to
link the observation with plasma L-arginine concentration and urinary c-GMP excretion (AIM
2). Based on extensive experience at Mayo Clinic of using oral L-arginine, we expect to
demonstrate no clinically significant adverse events with L-arginine (AIM 3). The data from
the open label maintenance phase (AIM 4) will help gauge whether the short term benefit
shown in AIM 1 is sustainable for a longer time frame.
The significance of these studies is based on several factors: (1) Calcineurin
inhibitor-induced renal insufficiency is a major source of morbidity and mortality among LTx
recipients; (2) Once it is established, there is no effective treatment for calcineurin
inhibitor-induced renal insufficiency; and (3) If the results of this study support our
hypothesis, we will be able to embark upon a full scale, randomized trial of long-term oral
L-arginine supplement using GFR as the end point. Such a study will be able to answer
whether a simple amino acid supplement may prevent calcineurin inhibitor nephrotoxicity,
making a fundamental difference in morbidity, mortality and quality of life of our patients,
who have undergone a life-changing procedure, namely liver transplantation.
1. Informed written consent
2. Ages 18+ at the time of entry into the study
3. Recipient of primary liver transplantation from a deceased or live donor
4. Stable with satisfactory allograft function
1. Total bilirubin < 2.5 mg/dl and
2. Aminotransferase < x 3 upper limit of normal (e.g., ALT<120 IU/mL)
5. Serum creatinine < 2.5 mg/dl without dialysis
6. Maintenance immunosuppression including tacrolimus or cyclosporine
7. Stable hemodynamic function
1. Systolic blood pressure > 100 mmHg
2. Resting pulse rate < 100
1. Recipient of combined liver-kidney transplantation
2. Prior organ transplantation (i.e., exposure to calcineurin inhibitors)
3. Established primary renal disease with active urinary sediments
4. On-going renal replacement therapy
5. Pulmonary hypertension (e.g., portopulmonary hypertension)
6. Iodine allergy
7. Other systemic illness (e.g., infection) that require hospitalization care beyond 2
weeks after LTx